The unifying focus of the proposed research is to characterize the mechanisms involved in cerebral ischemia. The two specific areas of study will be: 1.Cerebral autoregulation and its abnormalities 2.The mechanism of selective vulnerability of neurons in the brain during ischemia Cerebral autoregulation has been defined as the ability of the brain to maintain cerebral blood flow relatively constant during alteration in cerebral perfusion pressure. New methodology has been developed by the candidate and his advisor to measure autoregulation noninvasively in humans. The focus of the proposed research will be to further validate this method of measuring autoregulation and apply it to obtaining clinical measurements in patients suffering from closed head injury and eventually also to patients with cerebrovascular disease. The methodology utilizes continuous online bilateral monitoring of middle cerebral artery velocity using transcranial Doppler. A second aim of the present proposal is to study cellular mechanisms involved in selective vulnerability of neurons during anoxia and ischemia using neuronal organotypic cultures. The ischemia assay using this culture technique was originally developed by the candidate. It has been demonstrated using this model that selective damage to CA1 neurons can be produced in a system without a vascular supply. Thus, this system will allow the detailed study of pharmacological agents designed to protect the brain from selective neuronal cell loss during anoxia and ischemia. Further understanding of this phenomena and the development of cerebral protective agents may have vast implications in the care of patients. The unifying theme of this proposal is to study basic mechanisms which have been identified as significant in contributing to ischemia in brain injured patients and patients with cerebrovascular disease. Thus, this research may have a profound impact on the care of patients by providing information on basic mechanisms involved in ischemia and thereby lay the ground work for possible pharmacologic interventions. By developing expertise in studying these basic mechanisms, the candidate work toward establishing himself as an independent investigator.